From Diagnosis to Results: Navigating the Modern NSCLC Testing Journey

In non-small cell lung cancer (NSCLC), diagnostic evaluation has evolved beyond simply distinguishing between small-cell and non-small cell disease.¹ It serves as the basis for precise histologic classification, staging, molecular profiling, and ultimately, treatment selection.^1-3 Every decision surrounding tissue acquisition therefore influences not only the initial diagnosis, but also the ability to obtain the future molecular information needed to guide therapy decisions throughout a patient’s care.⁴ For oncologists, this creates a familiar tension: the same limited tissue sample must answer an expanding number of clinical questions, and the consequences of inadequate tissue can be significant.⁵  

Comprehensive biomarker testing begins with obtaining sufficient tissue to support both diagnosis and molecular characterization.⁴ The initial biopsy provides essential information regarding tumor subtype classification—whether the tumor is non-small cell, and if so, whether it is squamous or nonsquamous— and should yield sufficient, high-quality tissue for biomarker testing.⁴ This has become increasingly important as biomarker-informed treatment approaches influence therapy selection across multiple stages of lung cancer care.³ When actionable biomarkers are identified, biomarker-directed therapy may offer important patient-centered benefits, including improved clinical outcomes, greater tolerability, and reduced toxicity compared with conventional systemic approaches.⁶  

The challenge is that tissue is finite. Many patients with NSCLC are diagnosed using small biopsies, cytology specimens, or samples from difficult-to-access lesions.^3,7 Tumor cellularity may be limited, and additional diagnostic studies can consume material before molecular testing is complete.³ Tissue insufficiency can lead to incomplete biomarker results, reflexive use of alternative testing strategies, repeat biopsy, and delays in decision-making.⁵ For a patient with advanced disease who is symptomatic or clinically deteriorating, waiting for repeat tissue or delayed biomarker results can create uncertainty at precisely the moment when timely treatment selection is most important. 

This is where tissue stewardship becomes clinically relevant. The concept is not abstract; it is a practical approach to preserving diagnostic and molecular options for the patient in need of answers.⁵ Tissue stewardship starts before the biopsy takes place. The oncologist, proceduralist, and pathology team should understand that the goal is not only diagnosis, but also  molecular characterization.^4-6 Communication before tissue acquisition may help determine the most appropriate biopsy site and approach, particularly when multiple lesions are available or when a specimen may need to support broad testing.⁶ Ideally, biopsy planning occurs with molecular testing already in mind, allowing the proceduralist and pathology team to anticipate tissue requirements before the first sample is obtained.^4,6  

Stewardship also extends to the workflow after tissue acquisition. Minimizing unnecessary tissue exhaustion, reserving material for molecular testing, and selecting efficient testing strategies can help preserve tissue for current and future clinical questions.5,6 Multigene panel testing may reduce the need for multiple sequential assays when comprehensive profiling is clinically appropriate.⁵  When tissue is limited, thoughtful allocation of available material becomes increasingly important to maximize the likelihood of obtaining complete molecular information.⁴  

For oncologists, the key takeaway is that tissue stewardship is a shared responsibility. It requires coordination among oncology, pathology, pulmonology, interventional radiology, thoracic surgery, and the molecular laboratory.⁶ A well-planned biopsy supported by thoughtful tissue stewardship creates the foundation upon which every subsequent biomarker decision is built.⁵  

1. Ofiara LM, Navasakulpong A, Ezer N, Gonzalez AV. The importance of a satisfactory biopsy for the diagnosis of lung cancer in the era of personalized treatment. Curr Oncol. 2012;19(suppl 1):S16-S23. doi:10.3747/co.19.1062.  

2. Li W, Liu JB, Hou LK, et al. Liquid biopsy in lung cancer: significance in diagnostics, prediction, and treatment monitoring. Mol Cancer. 2022;21:25. doi:10.1186/s12943-022-01505-z.  

3. Nooreldeen R, Bach H. Current and future development in lung cancer diagnosis. Int J Mol Sci. 2021;22(16):8661. doi:10.3390/ijms22168661.  

4. Kerr KM, Bubendorf L, Lopez-Rios F, et al. Optimizing tissue stewardship in non-small cell lung cancer to support molecular characterization and treatment selection: statement from a working group of thoracic pathologists. Histopathology. 2024;84(3):429-439. doi:10.1111/his.15078. 

5. Ascierto PA, Bifulco C, Palmieri G, Peters S, Sidiropoulos N. Preanalytic variables and tissue stewardship for reliable next-generation sequencing (NGS) clinical analysis. J Mol Diagn. 2019;21(5):756-767. doi:10.1016/j.jmoldx.2019.05.004.  

6. Penault-Llorca F, Socinski MA. Emerging molecular testing paradigms in non-small cell lung cancer management—current perspectives and recommendations. Oncologist. 2025;30(3):oyae357. doi:10.1093/oncolo/oyae357. 

7. Hofman P. What is new in biomarker testing at diagnosis of advanced non-squamous non-small cell lung carcinoma? Implications for cytology and liquid biopsy. J Mol Pathol. 2021;2(2):147-172. doi:10.3390/jmp2020015.